WO2020171055A1 - Benzazepine derivative alcoholate or crystal thereof - Google Patents

Benzazepine derivative alcoholate or crystal thereof Download PDF

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WO2020171055A1
WO2020171055A1 PCT/JP2020/006243 JP2020006243W WO2020171055A1 WO 2020171055 A1 WO2020171055 A1 WO 2020171055A1 JP 2020006243 W JP2020006243 W JP 2020006243W WO 2020171055 A1 WO2020171055 A1 WO 2020171055A1
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crystal
compound
characteristic peaks
alcohol
characteristic
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PCT/JP2020/006243
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French (fr)
Japanese (ja)
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宣慶 春日井
和包 長井
齊藤　幸治
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株式会社 三和化学研究所
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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to an alcoholate of a benzazepine derivative or a crystal thereof.
  • N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3 4,5-Tetrahydro-1H-benzo[b]azepine-4-carboxamide is a compound having a V2 receptor agonistic action, and is effective in preventing or treating nocturia.
  • a chiral compound of the compound and a method for producing the same are disclosed in Patent Document 1. Further, intermediates of the compound are reported in Patent Document 2, Patent Document 3 and Non-Patent Document 1.
  • Patent Document 1 N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H).
  • -Pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide chiral compound was prepared and analyzed.
  • the compound was amorphous (amorphous).
  • Amorphous is known to be in a thermodynamically non-equilibrium metastable state, and generally has a high solubility and a high dissolution rate, but is low in stability and is often unfavorable in terms of drug development.
  • an object of the present invention is to increase the applicability as a drug substance to (S)-N-[(S)-1-hydroxypropan-2-yl]-4 represented by the formula (I).
  • -Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide It is to provide an alcohol solvate or a crystal thereof.
  • the inventors of the present invention have made extensive studies, and found that when the optically active benzazepine derivative represented by the formula (I) was used as a specific alcohol solvate, it could be isolated as a crystal, and the present invention was made. It came to completion.
  • the main configuration of the present invention is as follows.
  • an alcoholate and a crystal could not be obtained.
  • Formula (I) An alcoholate of the compound shown by or a crystal thereof.
  • Infrared absorption spectrum as wavenumber ( ⁇ 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1635 cm -1, or 948cm -1, 1096cm -1, 1240cm -1 and 1384cm -
  • the alcohol solvate crystal according to any one of [4] to [6], which exhibits a characteristic absorption peak in 1 .
  • the spacing d is 10.0 ⁇ 0.33 ⁇ , 7.3 ⁇ 0.18 ⁇ , 6.2 ⁇ 0.13 ⁇ , 4.9. Shows characteristic peaks at ⁇ 0.08 ⁇ and 4.1 ⁇ 0.06 ⁇ , or 10.0 ⁇ 0.33 ⁇ , 9.4 ⁇ 0.30 ⁇ , 7.3 ⁇ 0.18 ⁇ , 6.2 ⁇ 0.13 ⁇ , 5.9 ⁇ 0.12 ⁇ , 4.9 ⁇ 0.08 ⁇ , 4.3 ⁇ 0.06 ⁇ , 4.1 ⁇ 0.06 ⁇ and 3.9 ⁇ 0.05 ⁇
  • Infrared absorption spectrum as wavenumber ( ⁇ 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1623cm -1, or 1084cm -1, 1241cm -1, and 1384cm -1, wherein The crystal of the alcohol solvate according to any of [8] to [10], which exhibits a specific absorption peak.
  • [15] In the infrared absorption spectrum, as wavenumber ( ⁇ 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1580 cm -1, or 966cm -1, characteristic of 1094 cm -1 and 1384cm -1
  • a pharmaceutical composition comprising the alcoholate or the crystal thereof according to any one of [1] to [15].
  • an alcoholate of an optically active benzazepine derivative represented by the formula (I) can be isolated as crystals.
  • 1 shows a powder X-ray diffraction pattern of the compound obtained in Example 1.
  • 1 shows an infrared absorption spectrum of the compound obtained in Example 1.
  • 3 shows a powder X-ray diffraction pattern of the compound obtained in Example 2.
  • 2 shows an infrared absorption spectrum of the compound obtained in Example 2.
  • 3 shows a powder X-ray diffraction pattern of the compound obtained in Example 3.
  • 3 shows an infrared absorption spectrum of the compound obtained in Example 3.
  • 3 shows a powder X-ray diffraction pattern of the compound of Comparative Example 3.
  • the hygroscopic curve of the compound of Example 1, Example 2 and the reference example 1 in a hygroscopic property test is shown.
  • the vertical axis of the figure shows the amount of moisture absorption (%), and the horizontal axis shows the relative humidity (%RH).
  • One embodiment of the present invention is an alcohol solvate of the compound of formula (I).
  • the compound represented by the formula (I) is a V2 receptor agonist.
  • the compound represented by formula (I) is referred to as compound (I).
  • Compound (I) (free non-solvate) has not been obtained as a crystal at this time, but it can be obtained as a solvate with a specific alcohol.
  • Alcohol solvate refers to a complex formed by compound (I) (solute) and alcohol (solvent).
  • the alcohol is preferably a linear or branched C 1 -C 5 alcohol, more preferably a linear or branched C 1 -C 3 alcohol, and a linear or branched C 2 -C such as ethanol, isopropanol or normal propanol. 3 alcohol is particularly preferred.
  • compound (I) crystals other than alcohol solvate have not been obtained at present.
  • the alcohol content is preferably 0.1-fold to 2-fold, more preferably 0.5- to 1.5-fold, and most preferably 1-fold by molar ratio of compound (I).
  • the content of alcohol in the compound can be specified by a thermogravimetric measuring device, gas chromatography, nuclear magnetic resonance device, or the like.
  • the crystal of the alcoholate of the compound (I) shows the following characteristic peaks in the powder X-ray diffraction as the 2 ⁇ value or the interplanar spacing d.
  • the crystal of the isopropanol solvate of the compound (I) shows a characteristic peak at 17.5° and 18.0° as a 2 ⁇ value in a powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation, or 8 It preferably exhibits characteristic peaks at 0.5°, 14.8°, 18.0° and 21.0°, and 8.5°, 11.9°, 14.1°, 14.8°, 17 It is more preferable to show characteristic peaks at 0.5°, 18.0° and 21.0°, and 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, More preferably, it exhibits characteristic peaks at 18.0°, 19.0°, 20.7°, 21.0°, 22.8° and 24.6°.
  • characteristic peaks at 5.1 ⁇ and 4.9 ⁇ are shown, or 10.3 ⁇ , 6.0 ⁇ , 4.9 ⁇ and It is preferable to show a characteristic peak at 4.2 ⁇ , 10.3 ⁇ , 7.4 ⁇ , 6.3 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ and 4.2 ⁇ More preferably, 10.3 ⁇ , 7.4 ⁇ , 6.3 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ , 4.7 ⁇ , 4.3 ⁇ , 4.2 ⁇ , 3.9 ⁇ and 3.6 ⁇ More preferably, it exhibits a peak.
  • the crystals of the ethanol solvate of compound (I) have a 2 ⁇ value of 8.9°, 12.1°, 14.3°, 18.2° in the powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation. And 21.4° are preferable, and 8.9°, 9.4°, 12.1°, 14.3°, 15.1°, 18.2°, 20.9° are preferable. More preferably, it exhibits characteristic peaks at 21.4° and 23.1°. Further, in the powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation, characteristic peaks are shown as the interplanar spacing d at 10.0 ⁇ , 7.3 ⁇ , 6.2 ⁇ , 4.9 ⁇ and 4.1 ⁇ . Preferably, 10.0 ⁇ , 9.4 ⁇ , 7.3 ⁇ , 6.2 ⁇ , 5.9 ⁇ , 4.9 ⁇ , 4.3 ⁇ , 4.1 ⁇ and 3.9 ⁇ are more preferable.
  • the crystals of the normal propanol solvate of compound (I) are characterized by 2 ⁇ values of 17.3°, 18.0° and 18.8° in a powder X-ray diffraction spectrum (pattern) using CuK ⁇ radiation. It preferably exhibits peaks or characteristic peaks at 8.5°, 14.8°, 18.0° and 21.0°, such as 8.5°, 14.8°, 17.3°, It is more preferable to show characteristic peaks at 18.0°, 18.8° and 21.0°, and 8.5°, 11.9°, 14.3°, 14.8°, 17.3°. , 18.0°, 18.8°, 21.0°, 22.2°, 22.7°, 23.0° and 24.5° are more preferable.
  • characteristic peaks at 5.1 ⁇ , 4.9 ⁇ and 4.7 ⁇ , 10.4 ⁇ , 6.0 ⁇ It is preferable to show characteristic peaks at 4.9 ⁇ and 4.2 ⁇ , and it is preferable to show characteristic peaks at 10.4 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ , 4.7 ⁇ and 4.2 ⁇ . More preferably, 10.4 ⁇ , 7.4 ⁇ , 6.2 ⁇ , 6.0 ⁇ , 5.1 ⁇ , 4.9 ⁇ , 4.7 ⁇ , 4.2 ⁇ , 4.0 ⁇ , 3.9 ⁇ and 3.6 ⁇ More preferably, it exhibits a peak.
  • the 2 ⁇ value and the d-spacing value are selected from the characteristic peaks among the X-ray peaks, and the crystal structure is not necessarily limited to these values, and peaks other than these are included. May be. Further, in general, when crystals are measured by powder X-ray analysis, the peak may have some measurement error depending on the measuring equipment, the measurement conditions, and the like.
  • the 2 ⁇ value is preferably within ⁇ 0.3°, more preferably within ⁇ 0.2°, even more preferably within ⁇ 0.1°.
  • a 2 ⁇ value shows a characteristic peak at 17.5°
  • the error range of the surface spacing d value means a range calculated from the error range of the 2 ⁇ value described above.
  • the surface spacing d shows a characteristic peak at 5.1 ⁇
  • the surface spacing d is 5 It is preferable that "there is a characteristic peak at .01 ⁇ to 5.19 ⁇ ”, and it is more preferable that "there is a characteristic peak at 5.04 ⁇ to 5.16 ⁇ as the inter-spacing d”. It is more preferable that “a characteristic peak appears at 5.07 ⁇ to 5.13 ⁇ ”, and the same applies to other peaks.
  • the crystal of the alcoholate of compound (I) preferably has the following characteristic absorption peak in the infrared absorption spectrum.
  • the crystal of the isopropanol solvate of the compound (I) preferably has characteristic absorption peaks near wave numbers of 1535 cm ⁇ 1 and 1635 cm ⁇ 1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 948 cm -1 , 1096 cm -1 , 1240 cm -1 and 1384 cm -1 .
  • Crystals of the ethanol solvate of compound (I) preferably have characteristic absorption peaks near wave numbers of 1535 cm ⁇ 1 and 1623 cm ⁇ 1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 1084 cm -1 , 1241 cm -1 and 1384 cm -1 .
  • the crystals of the normal propanol solvate of compound (I) preferably have characteristic absorption peaks near wave numbers of 1535 cm -1 and 1580 cm -1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 966 cm -1 , 1094 cm -1 and 1384 cm -1 .
  • the above-mentioned wave number values are selected from characteristic wave number scales, and are not necessarily limited only by these values, and wave number scales other than these may be included.
  • some measurement error may occur due to measurement equipment or measurement conditions, and therefore some error should be taken into account in specifying the wave number.
  • Within ⁇ 0.8% is preferable, and within ⁇ 0.5% is more preferable.
  • the crystal of the alcoholate of the compound (I) of the present invention is not only specified as a characteristic peak as described above in the powder X-ray diffraction as the 2 ⁇ value or the interplanar spacing d, but also the powder X In addition to the characteristic peak in line diffraction, it can be specified as having a characteristic absorption peak as described above in the infrared absorption spectrum.
  • the alcoholate of compound (I) or a crystal thereof can be produced, for example, by the following method.
  • Compound (I) can be produced by the methods described in Patent Documents 1 to 3, and the like.
  • the alcoholate of compound (I) can be obtained by a conventional method for producing an alcoholate. Specifically, the alcoholate of the compound (I) is obtained by mixing the amorphous compound (I) and the alcohol while heating, if necessary, and then cooling the mixture while stirring or leaving it to crystallize. Can be obtained by It is desirable that the cooling be carried out while adjusting the cooling rate as necessary in consideration of the influence on the crystal quality and grain size.
  • cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable.
  • alcohols used in these methods include ethanol, normal propanol and isopropanol.
  • the alcohol may be hydrous.
  • the amount of alcohol used is preferably 3 to 20 times by mass, more preferably 5 to 10 times by mass, relative to the compound (I).
  • Crystals of the alcoholate of compound (I) can also be obtained by adding seed crystals to an alcohol solution of compound (I). Seed crystals (eg, crystals of isopropanol solvate of compound (I)) may be added during crystallization.
  • the temperature at which the seed crystal is added is not particularly limited, but is preferably 0 to 80°C, more preferably 40 to 70°C, further preferably 50 to 65°C.
  • the amount of seed crystals added is preferably 0.0001 to 0.1 mol, and more preferably 0.005 to 0.01 mol, per 1 mol of compound (I).
  • the crystals obtained above can be isolated by filtration, washed if necessary, and dried according to the usual procedure.
  • the solvent used for washing the crystals the same solvent as used in the crystallization can be used.
  • the alcoholate of compound (I) can be obtained as crystals, it can be easily handled as a medicine. In addition, all of the alcoholates of compound (I) have lower hygroscopicity than the amorphous form of compound (I), and are good as pharmaceuticals in terms of quality control. Therefore, according to the present invention, an alcoholate of compound (I) which is useful as a drug substance can be provided.
  • the pharmaceutical composition according to one embodiment of the present invention can be prepared by mixing a pharmaceutically acceptable additive with an alcoholate of compound (I) or a crystal thereof.
  • the pharmaceutical composition of the present invention can be prepared by a known method, for example, the method described in the general rules for preparation of the 17th edition of the Japanese Pharmacopoeia.
  • the present invention includes a mixture with the compound (I) in an amorphous form as long as it contains an alcoholate of the compound (I) or a crystal thereof in an arbitrary ratio.
  • the content of the alcoholate of the compound (I) or the crystal thereof in the active ingredient is preferably 20% or more, more preferably 30% or more, further preferably 40% or more, and 100%. Is most preferable.
  • the alcoholate of the compound (I) of the present invention or a crystal thereof acts as a V2 receptor agonist, central diabetes insipidus, nocturnal enuresis, nocturia, overactive bladder, hemophilia, or von Wille It can be used as a medicine for the prevention or treatment of Brand's disease.
  • Compound (I) selectively acts on the V2 receptor and is therefore advantageous from the viewpoint of side effects.
  • the compound (I) has a lower inhibitory effect on the drug-metabolizing enzymes CYP3A4 and CYP2C9 than the conventionally known compounds having a V2 receptor agonistic action, and further has physical properties as a drug such as solubility and membrane permeability. Since it also has excellent properties in terms of surface and dynamic aspects such as plasma clearance and distribution volume, it can be used safely.
  • the amount of the alcohol solvate of the compound (I) of the present invention or its crystal contained as an active ingredient of a drug is not particularly limited and is appropriately selected from a wide range.
  • the dose of the alcohol solvate of Compound (I) or the crystal thereof is appropriately determined depending on the usage, the age of the patient, sex and other conditions, and the degree of the disease. Approximately 1 ⁇ g to 100 mg, preferably approximately 10 ⁇ g to 20 mg, and more preferably approximately 50 ⁇ g to 5 mg per kg, which can be appropriately administered in 1 to 4 divided doses per day. However, since the dose and frequency are determined in consideration of the degree of the condition to be treated, the selection of the compound to be administered and the relevant circumstances including the selected administration route, the above dose range and frequency are not limited to the above. It does not limit the scope of the invention.
  • Compound (I) produces metabolites as shown below when administered to a living body.
  • the powder X-ray diffraction measurement, thermogravimetric measurement, infrared absorption spectrum measurement, and water equilibrium measurement were performed under the following measurement conditions.
  • Thermogravimetric measurement The TGA thermogram was performed using Perkin Elmer (Pyris1-TGA). The measurement conditions were 20 mL/min of nitrogen gas, isothermal for 1 minute at an initial temperature of 80° C., then increased to 170° C. at 5° C./minute, and isothermal for 1 minute at 170° C.
  • the infrared absorption spectrum was measured using Perkin Elmer (Spectrum One). Measurement conditions, the measurement range 4000 ⁇ 400 cm -1, resolution 4.00 cm -1, scan number was 4 times.
  • the moisture equilibrium measurement was performed using TA Instruments (SGA-100).
  • the measurement conditions were a measurement temperature of 25° C., a maximum measurement time of 210 minutes, a water equilibrium weight of 0.005% by weight/5 minutes, and 50 to 95% RH from the start of humidification to the end point.
  • the drying conditions were a drying temperature of 60° C., a temperature rising rate of 5° C./minute, a maximum drying time of 60 minutes, and a water equilibrium weight of 0.01% by weight/2 minutes.
  • FIG. 7 shows the powder X-ray diffraction spectrum of the compound (I) obtained in the first to sixth steps. No clear peak was observed in the X-ray diffraction pattern, and the compound (I) of Reference Example 1 was found to be amorphous.
  • Example 1 Isopropanol solvate of compound (I) To 5.0 g of the amorphous compound (I) of Reference Example 1, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with chilled isopropanol and dried overnight at 40° C. to give 4.9 g of a white solid.
  • the powder X-ray diffraction spectrum and infrared absorption spectrum of the compound obtained in Example 1 are shown in FIG. 1 and FIG. 2, respectively.
  • the characteristic peaks shown in Table 1 were shown as the diffraction angle (2 ⁇ ) or as the interplanar spacing d.
  • the obtained compound was crystalline.
  • Example 2 Ethanol solvate of compound (I) To 0.15 g of the amorphous compound (I) of Reference Example 1, 2 mL of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. After the precipitated suspension was dissolved by heating, it was allowed to cool to room temperature and stirred at 5°C overnight. The suspension was filtered, washed with cold ethanol, and dried at 40° C. overnight to give white solid 0.07 g.
  • the powder X-ray diffraction spectrum and infrared absorption spectrum of the compound obtained in Example 2 are shown in FIG. 3 and FIG. 4, respectively.
  • the characteristic peaks shown in Table 2 were shown as the diffraction angle (2 ⁇ ) or as the interplanar spacing d.
  • the obtained compound was crystalline.
  • Example 3 Normal propanol solvate of compound (I) To 5.0 g of amorphous compound (I) of Reference Example 1, 31 mL of normal propanol was added, and the mixture was stirred at room temperature for 15 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with cold normal propanol, and dried at 40° C. overnight to obtain 4.1 g of a white solid.
  • a powder X-ray diffraction spectrum and an infrared absorption spectrum of the compound obtained in Example 3 are shown in FIG. 5 and FIG. 6, respectively.
  • the characteristic peaks shown in Table 3 were shown as the diffraction angle (2 ⁇ ) or as the interplanar spacing d.
  • the obtained compound was crystalline.
  • Comparative compound 1 the compound represented by the above formula (II)
  • Example 93 of Patent Document 1 The compound described in Example 93 of Patent Document 1 (Comparative compound 1: the compound represented by the above formula (II)) was obtained by the production method described in Patent Document 1.
  • the solvent shown in Table 4 was added, and the mixture was stirred at room temperature, dissolved by heating, allowed to cool to room temperature, and allowed to stand at 5° C. overnight.
  • Example 72 of Patent Document 1 The compound described in Example 72 of Patent Document 1 (Comparative compound 2: compound represented by the above formula (III)) was obtained by the production method described in Patent Document 1.
  • the solvent shown in Table 5 was added to 10 mg of the obtained comparative compound 2, and the mixture was stirred at room temperature, dissolved by heating, allowed to cool to room temperature, and allowed to stand at 5° C. overnight. However, it was not possible to obtain a solvate of Comparative Compound 2 or a crystal thereof.
  • Test Example 1 Hygroscopicity Test The compound of Example 1 (isopropanol solvate of compound (I)), the compound of Example 2 (ethanol solvate of compound (I)), and the compound of Reference Example 1 (amorphous compound) The hygroscopicity of (I)) was compared under the following conditions.
  • a quartz sample holder was hooked on a balance, and about 10 mg of the compounds of Examples 1 and 2 and Reference Example 1 were put therein. After registering the sample mass, a test was carried out with a water balance measuring device to measure the rate of change of mass at each relative humidity.
  • Test Example 1 The results of Test Example 1 are shown in FIG. It was confirmed that the compounds of Examples 1 and 2 were less likely to absorb moisture and were excellent in storage stability as compared with the compound of Reference Example 1.
  • an alcoholate of an optically active benzazepine derivative represented by the formula (I) can be isolated as a crystal.

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Abstract

This invention provides an alcoholate of (S)-N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide represented by formula (I), or a crystal thereof, which is applicable as an active ingredient of a pharmaceutical drug.

Description

ベンゾアゼピン誘導体のアルコール和物又はその結晶Alcoholate of benzazepine derivative or its crystal
　本発明は、ベンゾアゼピン誘導体のアルコール和物又はその結晶に関する。 The present invention relates to an alcoholate of a benzazepine derivative or a crystal thereof.
　Ｎ－［（Ｓ）－１－ヒドロキシプロパン－２－イル］－４－メチル－１－［２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル］－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボキサミドは、Ｖ２受容体作動作用を有する化合物であり、夜間頻尿等の予防又は治療に有効である。当該化合物のキラル体及びその製造方法は、特許文献１に開示されている。また、当該化合物の中間体が特許文献２、特許文献３及び非特許文献１に報告されている。 N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3 4,5-Tetrahydro-1H-benzo[b]azepine-4-carboxamide is a compound having a V2 receptor agonistic action, and is effective in preventing or treating nocturia. A chiral compound of the compound and a method for producing the same are disclosed in Patent Document 1. Further, intermediates of the compound are reported in Patent Document 2, Patent Document 3 and Non-Patent Document 1.
国際公開第２０１４／１０４２０９号International Publication No. 2014/104209 特開２０１６－０４０３３８号JP-A-2016-040338 特開２０１６－１８５９９３号JP-A-2016-185993
　本発明者らが、特許文献１に記載の方法でＮ－［（Ｓ）－１－ヒドロキシプロパン－２－イル］－４－メチル－１－［２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル］－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボキサミドのキラル体を調製し、分析したところ、当該化合物はアモルファス（非晶質固体）であった。アモルファスは、熱力学的に非平衡な準安定状態であることが知られており、一般的に溶解度及び溶解速度は大きくなるが、安定性が低く、医薬品開発の面で好ましくない場合が多い。したがって、本発明の目的は、医薬品原薬としての利用可能性が高くなる、式（Ｉ）で表される（Ｓ）－Ｎ－［（Ｓ）－１－ヒドロキシプロパン－２－イル］－４－メチル－１－［２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル］－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボキサミドのアルコール和物又はその結晶を提供することである。
Figure JPOXMLDOC01-appb-C000002
 The present inventors have investigated the method described in Patent Document 1 by using N-[(S)-1-hydroxypropan-2-yl]-4-methyl-1-[2-methyl-4-(3-methyl-1H). -Pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide chiral compound was prepared and analyzed. As a result, the compound was amorphous (amorphous). Solid). Amorphous is known to be in a thermodynamically non-equilibrium metastable state, and generally has a high solubility and a high dissolution rate, but is low in stability and is often unfavorable in terms of drug development. Therefore, an object of the present invention is to increase the applicability as a drug substance to (S)-N-[(S)-1-hydroxypropan-2-yl]-4 represented by the formula (I). -Methyl-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide It is to provide an alcohol solvate or a crystal thereof.
Figure JPOXMLDOC01-appb-C000002
　上記課題に鑑み、本発明者らが鋭意検討したところ、式（Ｉ）で表される光学活性なベンゾアゼピン誘導体を特定のアルコール和物としたところ、結晶として単離できることを見出し、本発明を完成するに至った。本発明の主な構成は以下の通りである。尚、式（Ｉ）で表されるベンゾアゼピン誘導体の構造類似化合物においては、アルコール和物及び結晶を得ることはできなかった。 In view of the above problems, the inventors of the present invention have made extensive studies, and found that when the optically active benzazepine derivative represented by the formula (I) was used as a specific alcohol solvate, it could be isolated as a crystal, and the present invention was made. It came to completion. The main configuration of the present invention is as follows. In addition, in the structurally similar compound of the benzazepine derivative represented by the formula (I), an alcoholate and a crystal could not be obtained.
［１］　式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
 で示される化合物のアルコール和物又はその結晶。
［２］　アルコールの含有量が、前記式（Ｉ）で示される化合物に対してモル比で０．１倍量から２倍量である、［１］に記載のアルコール和物又はその結晶。
［３］　前記アルコールが、エタノール、イソプロパノール、及びノルマルプロパノールからなる群より選択される、［１］又は［２］に記載のアルコール和物又はその結晶。
［４］　前記アルコールがイソプロパノールである、［３］に記載のアルコール和物又はその結晶。 [1] Formula (I):
Figure JPOXMLDOC01-appb-C000003
 An alcoholate of the compound shown by or a crystal thereof.
[2] The alcohol solvate or the crystal thereof according to [1], wherein the alcohol content is 0.1 to 2 times the molar amount of the compound represented by the formula (I).
[3] The alcohol solvate or the crystal thereof according to [1] or [2], wherein the alcohol is selected from the group consisting of ethanol, isopropanol, and normal propanol.
[4] The alcohol solvate or the crystal thereof according to [3], wherein the alcohol is isopropanol.
［５］　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、回折角度２θ±０．３°として、１７．５°及び１８．０°に特徴的なピークを示すか、８．５°、１４．８°、１８．０°及び２１．０°に特徴的なピークを示すか、８．５°、１１．９°、１４．１°、１４．８°、１７．５°、１８．０°及び２１．０°に特徴的なピークを示すか、又は８．５°、１１．９°、１４．１°、１４．８°、１７．５°、１８．０°、１９．０°、２０．７°、２１．０°、２２．８°及び２４．６°に特徴的なピークを示す、［４］に記載のアルコール和物の結晶。
［６］　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、５．１±０．０９Å及び４．９±０．０８Åに特徴的なピークを示すか、１０．３±０．３７Å、６．０±０．１２Å、４．９±０．０８Å及び４．２±０．０６Åに特徴的なピークを示すか、１０．３±０．３７Å、７．４±０．１９Å、６．３±０．１３Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å及び４．２±０．０６Åに特徴的なピークを示すか、又は１０．３±０．３７Å、７．４±０．１９Å、６．３±０．１３Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å、４．７±０．０７Å、４．３±０．０６Å、４．２±０．０６Å、３．９±０．０５Å及び３．６±０．０４Åに特徴的なピークを示す、［４］に記載のアルコール和物の結晶。
［７］　赤外線吸収スペクトルにおいて、波数（±０．５％）として、１５３５cm－１及び１６３５cm－１に特徴的な吸収ピークを示すか、又は９４８cm－１、１０９６cm－１、１２４０cm－１及び１３８４cm－１に特徴的な吸収ピークを示す、［４］～［６］のいずれかに記載のアルコール和物の結晶。 [5] In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, characteristic peaks are shown at 17.5° and 18.0° at a diffraction angle of 2θ±0.3°, or 8.5°. , 14.8°, 18.0° and 21.0° show characteristic peaks, or 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, 18 Shows characteristic peaks at 0.0° and 21.0° or 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, 18.0°, 19. The crystal of alcohol solvate according to [4], which shows characteristic peaks at 0°, 20.7°, 21.0°, 22.8° and 24.6°.
[6] In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, characteristic spacing peaks of 5.1±0.09Å and 4.9±0.08Å are shown as 10.3. Shows characteristic peaks at ±0.37Å, 6.0±0.12Å, 4.9±0.08Å and 4.2±0.06Å, 10.3±0.37Å, 7.4±0 .19Å, 6.3±0.13Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å and 4.2±0.06Å , Or 10.3±0.37Å, 7.4±0.19Å, 6.3±0.13Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å, 4.7 ± 0.07 Å, 4.3 ± 0.06 Å, 4.2 ± 0.06 Å, 3.9 ± 0.05 Å and 3.6 ± 0.04 Å [4] A crystal of the alcohol solvate described in.
In [7] Infrared absorption spectrum, as wavenumber (± 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1635 cm -1, or 948cm -1, 1096cm -1, 1240cm -1 and 1384cm - The alcohol solvate crystal according to any one of [4] to [6], which exhibits a characteristic absorption peak in 1 .
［８］　前記アルコールがエタノールである、［３］に記載のアルコール和物又はその結晶。
［９］　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、回折角度２θ±０．３°として、８．９°、１２．１°、１４．３°、１８．２°及び２１．４°に特徴的なピークを示すか、又は８．９°、９．４°、１２．１°、１４．３°、１５．１°、１８．２°、２０．９°、２１．４°及び２３．１°に特徴的なピークを示す、［８］に記載のアルコール和物の結晶。
［１０］　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、１０．０±０．３３Å、７．３±０．１８Å、６．２±０．１３Å、４．９±０．０８Å及び４．１±０．０６Åに特徴的なピークを示すか、又は１０．０±０．３３Å、９．４±０．３０Å、７．３±０．１８Å、６．２±０．１３Å、５．９±０．１２Å、４．９±０．０８Å、４．３±０．０６Å、４．１±０．０６Å及び３．９±０．０５Åに特徴的なピークを示す、［８］に記載のアルコール和物の結晶。
［１１］　赤外線吸収スペクトルにおいて、波数（±０．５％）として、１５３５cm－１及び１６２３cm－１に特徴的な吸収ピークを示すか、又は１０８４cm－１、１２４１cm－１、及び１３８４cm－１に特徴的な吸収ピークを示す、［８］～［１０］のいずれかに記載のアルコール和物の結晶。 [8] The alcohol solvate or the crystal thereof according to [3], wherein the alcohol is ethanol.
[9] In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, the diffraction angle 2θ±0.3° was 8.9°, 12.1°, 14.3°, 18.2° and 21. Shows a characteristic peak at 4° or 8.9°, 9.4°, 12.1°, 14.3°, 15.1°, 18.2°, 20.9°, 21.4 The crystal of the alcohol solvate according to [8], which shows characteristic peaks at ° and 23.1 °.
[10] In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, the spacing d is 10.0±0.33Å, 7.3±0.18Å, 6.2±0.13Å, 4.9. Shows characteristic peaks at ±0.08Å and 4.1±0.06Å, or 10.0±0.33Å, 9.4±0.30Å, 7.3±0.18Å, 6.2± 0.13Å, 5.9±0.12Å, 4.9±0.08Å, 4.3±0.06Å, 4.1±0.06Å and 3.9±0.05Å The crystal of the alcohol solvate described in [8].
In [11] Infrared absorption spectrum, as wavenumber (± 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1623cm -1, or 1084cm -1, 1241cm -1, and 1384cm -1, wherein The crystal of the alcohol solvate according to any of [8] to [10], which exhibits a specific absorption peak.
［１２］　前記アルコールがノルマルプロパノールである、［３］に記載のアルコール和物又はその結晶。
［１３］　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、回折角度２θ±０．３°として、１７．３°、１８．０°及び１８．８°に特徴的なピークを示すか、８．５°、１４．８°、１８．０°及び２１．０°に特徴的なピークを示すか、８．５°、１４．８°、１７．３°、１８．０°、１８．８°及び２１．０°に特徴的なピークを示すか、又は８．５°、１１．９°、１４．３°、１４．８°、１７．３°、１８．０°、１８．８°、２１．０°、２２．２°、２２．７°、２３．０°及び２４．５°に特徴的なピークを示す、［１２］に記載のアルコール和物の結晶。
［１４］　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、５．１±０．０９Å、４．９±０．０８Å及び４．７±０．０７Åに特徴的なピークを示すか、１０．４±０．３７Å、６．０±０．１２Å、４．９±０．０８Å及び４．２±０．０６Åに特徴的なピークを示すか、１０．４±０．３７Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å、４．７±０．０７Å及び４．２±０．０６Åに特徴的なピークを示すか、又は１０．４±０．３７Å、７．４±０．１９Å、６．２±０．１３Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å、４．７±０．０７Å、４．２±０．０６Å、４．０±０．０５Å、３．９±０．０５Å及び３．６±０．０４Åに特徴的なピークを示す、［１２］に記載のアルコール和物の結晶。
［１５］　赤外線吸収スペクトルにおいて、波数（±０．５％）として、１５３５cm－１及び１５８０cm－１に特徴的な吸収ピークを示すか、又は９６６cm－１、１０９４cm－１及び１３８４cm－１に特徴的な吸収ピークを示す、［１２］～［１４］のいずれかに記載のアルコール和物の結晶。
［１６］　［１］～［１５］のいずれかに記載のアルコール和物又はその結晶を含む医薬組成物。 [12] The alcohol solvate or the crystal thereof according to [3], wherein the alcohol is normal propanol.
[13] Does the powder X-ray diffraction spectrum (pattern) using CuKα radiation show characteristic peaks at 17.3°, 18.0°, and 18.8° at a diffraction angle of 2θ±0.3°? , 8.5°, 14.8°, 18.0° and 21.0° show characteristic peaks, or 8.5°, 14.8°, 17.3°, 18.0°, 18 Characteristic peaks at .8° and 21.0° or 8.5°, 11.9°, 14.3°, 14.8°, 17.3°, 18.0°, 18. The crystal of alcohol solvate according to [12], which shows characteristic peaks at 8°, 21.0°, 22.2°, 22.7°, 23.0°, and 24.5°.
[14] In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, the interplanar spacing d is 5.1±0.09Å, 4.9±0.08Å and 4.7±0.07Å Shows peaks, 10.4±0.37Å, 6.0±0.12Å, 4.9±0.08Å and 4.2±0.06Å, or 10.4±0 .37Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å, 4.7±0.07Å and 4.2±0.06Å , Or 10.4±0.37Å, 7.4±0.19Å, 6.2±0.13Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å, It shows characteristic peaks at 4.7±0.07Å, 4.2±0.06Å, 4.0±0.05Å, 3.9±0.05Å and 3.6±0.04Å, [12] A crystal of the alcohol solvate described in.
[15] In the infrared absorption spectrum, as wavenumber (± 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1580 cm -1, or 966cm -1, characteristic of 1094 cm -1 and 1384cm -1 The alcohol solvate crystal according to any one of [12] to [14], which exhibits various absorption peaks.
[16] A pharmaceutical composition comprising the alcoholate or the crystal thereof according to any one of [1] to [15].
　本発明によれば、式（Ｉ）で表される光学活性なベンゾアゼピン誘導体のアルコール和物を結晶として単離することができる。 According to the present invention, an alcoholate of an optically active benzazepine derivative represented by the formula (I) can be isolated as crystals.
実施例１で得られた化合物の粉末Ｘ線回折パターンを示す。1 shows a powder X-ray diffraction pattern of the compound obtained in Example 1. 実施例１で得られた化合物の赤外吸収スペクトルを示す。1 shows an infrared absorption spectrum of the compound obtained in Example 1. 実施例２で得られた化合物の粉末Ｘ線回折パターンを示す。3 shows a powder X-ray diffraction pattern of the compound obtained in Example 2. 実施例２で得られた化合物の赤外吸収スペクトルを示す。2 shows an infrared absorption spectrum of the compound obtained in Example 2. 実施例３で得られた化合物の粉末Ｘ線回折パターンを示す。3 shows a powder X-ray diffraction pattern of the compound obtained in Example 3. 実施例３で得られた化合物の赤外吸収スペクトルを示す。3 shows an infrared absorption spectrum of the compound obtained in Example 3. 比較例３の化合物の粉末Ｘ線回折パターンを示す。3 shows a powder X-ray diffraction pattern of the compound of Comparative Example 3. 吸湿性試験における実施例１、実施例２及び参考例１の化合物の吸湿曲線を示す。図の縦軸は吸湿量（％）を示し、横軸は、相対湿度（％ＲＨ）を示す。The hygroscopic curve of the compound of Example 1, Example 2 and the reference example 1 in a hygroscopic property test is shown. The vertical axis of the figure shows the amount of moisture absorption (%), and the horizontal axis shows the relative humidity (%RH).
　以下に、本発明の実施形態を更に詳細に説明する。ただし、本発明は以下の実施形態に限定されるものではない。 The embodiments of the present invention will be described in more detail below. However, the present invention is not limited to the following embodiments.
　本発明の一実施形態は、式（Ｉ）で表される化合物のアルコール和物である。
Figure JPOXMLDOC01-appb-C000004
 One embodiment of the present invention is an alcohol solvate of the compound of formula (I).
Figure JPOXMLDOC01-appb-C000004
　式（Ｉ）で表される化合物は、Ｖ２受容体作動薬である。以下、式（Ｉ）で表される化合物を化合物（Ｉ）という。化合物（Ｉ）（遊離の非溶媒和物）は、現時点では結晶として得られていないが、特定のアルコールとの溶媒和物とすることで結晶として得ることができる。 The compound represented by the formula (I) is a V2 receptor agonist. Hereinafter, the compound represented by formula (I) is referred to as compound (I). Compound (I) (free non-solvate) has not been obtained as a crystal at this time, but it can be obtained as a solvate with a specific alcohol.
　「アルコール和物」とは、化合物（Ｉ）（溶質）とアルコール（溶媒）とによって形成される複合体をいう。アルコールとしては、直鎖又は分岐のＣ１～Ｃ５アルコールが好ましく、直鎖又は分岐のＣ１～Ｃ３アルコールがより好ましく、エタノール、イソプロパノール又はノルマルプロパノール等の直鎖又は分岐のＣ２～Ｃ３アルコールが特に好ましい。なお、化合物（Ｉ）は、現時点ではアルコール和物以外の結晶は得られていない。 “Alcohol solvate” refers to a complex formed by compound (I) (solute) and alcohol (solvent). The alcohol is preferably a linear or branched C 1 -C 5 alcohol, more preferably a linear or branched C 1 -C 3 alcohol, and a linear or branched C 2 -C such as ethanol, isopropanol or normal propanol. 3 alcohol is particularly preferred. As for compound (I), crystals other than alcohol solvate have not been obtained at present.
　アルコールの含有量は、化合物（Ｉ）に対してモル比で０．１倍量から２倍量が好ましく、０．５倍量から１．５倍量がより好ましく、等倍量が最も好ましい。化合物中のアルコールの含有量は、熱重量測定装置、ガスクロマトグラフィー、核磁気共鳴装置等により特定することができる。 The alcohol content is preferably 0.1-fold to 2-fold, more preferably 0.5- to 1.5-fold, and most preferably 1-fold by molar ratio of compound (I). The content of alcohol in the compound can be specified by a thermogravimetric measuring device, gas chromatography, nuclear magnetic resonance device, or the like.
　化合物（Ｉ）のアルコール和物の結晶は、粉末Ｘ線回折において、２θ値として又は面間隔ｄとして下記の通りの特徴的なピークを示す。なお、面間隔ｄ［オングストローム（Å）］は、λ＝２ｄｓｉｎθの関係がある。ＣｕＫα線のλは１．５４Åなので、関係式により面間隔ｄ値を算出できる。 The crystal of the alcoholate of the compound (I) shows the following characteristic peaks in the powder X-ray diffraction as the 2θ value or the interplanar spacing d. The surface spacing d [angstrom (Å)] has a relationship of λ=2 dsin θ. Since the λ of the CuKα ray is 1.54Å, the interplanar spacing d value can be calculated by the relational expression.
　化合物（Ｉ）のイソプロパノール和物の結晶は、ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、２θ値として、１７．５°及び１８．０°に特徴的なピークを示すか、８．５°、１４．８°、１８．０°及び２１．０°に特徴的なピークを示すのが好ましく、８．５°、１１．９°、１４．１°、１４．８°、１７．５°、１８．０°及び２１．０°に特徴的なピークを示すのがより好ましく、８．５°、１１．９°、１４．１°、１４．８°、１７．５°、１８．０°、１９．０°、２０．７°、２１．０°、２２．８°及び２４．６°に特徴的なピークを示すのが更に好ましい。また、ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、５．１Å及び４．９Åに特徴的なピークを示すか、１０．３Å、６．０Å、４．９Å及び４．２Åに特徴的なピークを示すのが好ましく、１０．３Å、７．４Å、６．３Å、６．０Å、５．１Å、４．９Å及び４．２Åに特徴的なピークを示すのがより好ましく、１０．３Å、７．４Å、６．３Å、６．０Å、５．１Å、４．９Å、４．７Å、４．３Å、４．２Å、３．９Å及び３．６Åに特徴的なピークを示すのが更に好ましい。 The crystal of the isopropanol solvate of the compound (I) shows a characteristic peak at 17.5° and 18.0° as a 2θ value in a powder X-ray diffraction spectrum (pattern) using CuKα radiation, or 8 It preferably exhibits characteristic peaks at 0.5°, 14.8°, 18.0° and 21.0°, and 8.5°, 11.9°, 14.1°, 14.8°, 17 It is more preferable to show characteristic peaks at 0.5°, 18.0° and 21.0°, and 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, More preferably, it exhibits characteristic peaks at 18.0°, 19.0°, 20.7°, 21.0°, 22.8° and 24.6°. Further, in the powder X-ray diffraction spectrum (pattern) using CuKα radiation, as the interplanar spacing d, characteristic peaks at 5.1 Å and 4.9 Å are shown, or 10.3 Å, 6.0 Å, 4.9 Å and It is preferable to show a characteristic peak at 4.2Å, 10.3Å, 7.4Å, 6.3Å, 6.0Å, 5.1Å, 4.9Å and 4.2Å More preferably, 10.3Å, 7.4Å, 6.3Å, 6.0Å, 5.1Å, 4.9Å, 4.7Å, 4.3Å, 4.2Å, 3.9Å and 3.6Å More preferably, it exhibits a peak.
　化合物（Ｉ）のエタノール和物の結晶は、ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、２θ値として、８．９°、１２．１°、１４．３°、１８．２°及び２１．４°に特徴的なピークを示すのが好ましく、８．９°、９．４°、１２．１°、１４．３°、１５．１°、１８．２°、２０．９°、２１．４°及び２３．１°に特徴的なピークを示すのがより好ましい。また、ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、１０．０Å、７．３Å、６．２Å、４．９Å及び４．１Åに特徴的なピークを示すのが好ましく、１０．０Å、９．４Å、７．３Å、６．２Å、５．９Å、４．９Å、４．３Å、４．１Å及び３．９Åに特徴的なピークを示すのがより好ましい。 The crystals of the ethanol solvate of compound (I) have a 2θ value of 8.9°, 12.1°, 14.3°, 18.2° in the powder X-ray diffraction spectrum (pattern) using CuKα radiation. And 21.4° are preferable, and 8.9°, 9.4°, 12.1°, 14.3°, 15.1°, 18.2°, 20.9° are preferable. More preferably, it exhibits characteristic peaks at 21.4° and 23.1°. Further, in the powder X-ray diffraction spectrum (pattern) using CuKα radiation, characteristic peaks are shown as the interplanar spacing d at 10.0Å, 7.3Å, 6.2Å, 4.9Å and 4.1Å. Preferably, 10.0Å, 9.4Å, 7.3Å, 6.2Å, 5.9Å, 4.9Å, 4.3Å, 4.1Å and 3.9Å are more preferable.
　化合物（Ｉ）のノルマルプロパノール和物の結晶は、ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、２θ値として、１７．３°、１８．０°及び１８．８°に特徴的なピークを示すか、８．５°、１４．８°、１８．０°及び２１．０°に特徴的なピークを示すのが好ましく、８．５°、１４．８°、１７．３°、１８．０°、１８．８°及び２１．０°に特徴的なピークを示すのがより好ましく、８．５°、１１．９°、１４．３°、１４．８°、１７．３°、１８．０°、１８．８°、２１．０°、２２．２°、２２．７°、２３．０°及び２４．５°に特徴的なピークを示すのが更に好ましい。また、ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、５．１Å、４．９Å及び４．７Åに特徴的なピークを示すか、１０．４Å、６．０Å、４．９Å及び４．２Åに特徴的なピークを示すのが好ましく、１０．４Å、６．０Å、５．１Å、４．９Å、４．７Å及び４．２Åに特徴的なピークを示すのがより好ましく、１０．４Å、７．４Å、６．２Å、６．０Å、５．１Å、４．９Å、４．７Å、４．２Å、４．０Å、３．９Å及び３．６Åに特徴的なピークを示すのが更に好ましい。 The crystals of the normal propanol solvate of compound (I) are characterized by 2θ values of 17.3°, 18.0° and 18.8° in a powder X-ray diffraction spectrum (pattern) using CuKα radiation. It preferably exhibits peaks or characteristic peaks at 8.5°, 14.8°, 18.0° and 21.0°, such as 8.5°, 14.8°, 17.3°, It is more preferable to show characteristic peaks at 18.0°, 18.8° and 21.0°, and 8.5°, 11.9°, 14.3°, 14.8°, 17.3°. , 18.0°, 18.8°, 21.0°, 22.2°, 22.7°, 23.0° and 24.5° are more preferable. Further, in the powder X-ray diffraction spectrum (pattern) using CuKα radiation, as the interplanar spacing d, characteristic peaks at 5.1 Å, 4.9 Å and 4.7 Å, 10.4 Å, 6.0 Å, It is preferable to show characteristic peaks at 4.9Å and 4.2Å, and it is preferable to show characteristic peaks at 10.4Å, 6.0Å, 5.1Å, 4.9Å, 4.7Å and 4.2Å. More preferably, 10.4Å, 7.4Å, 6.2Å, 6.0Å, 5.1Å, 4.9Å, 4.7Å, 4.2Å, 4.0Å, 3.9Å and 3.6Å More preferably, it exhibits a peak.
　上記２θ値及び面間隔ｄ値は、Ｘ線ピークのうち、特徴的なピークを選択したものであり、結晶構造は必ずしもこれらの値だけによって限定されるものではなく、これら以外のピークが含まれていてもよい。また一般に、結晶を粉末Ｘ線解析により測定した場合、そのピークは、測定機器又は測定条件等により、多少の測定誤差が生じ得る。 The 2θ value and the d-spacing value are selected from the characteristic peaks among the X-ray peaks, and the crystal structure is not necessarily limited to these values, and peaks other than these are included. May be. Further, in general, when crystals are measured by powder X-ray analysis, the peak may have some measurement error depending on the measuring equipment, the measurement conditions, and the like.
　結晶の同定には多少の誤差が考慮されるべきであり、２θ値は、±０．３°以内が好ましく、±０．２°以内がより好ましく、±０．１°以内が更に好ましい。例えば、「２θ値として、１７．５°に特徴的なピークを示す」との記載の場合は、「２θ値として、１７．２°～１７．８°に特徴的なピークを示す」ことが好ましく、「２θ値として、１７．３°～１７．７°に特徴的なピークを示す」ことがより好ましく、「２θ値として、１７．４°～１７．６°に特徴的なピークを示す」ことが更に好ましく、他のピークについても同様である。 Some errors should be taken into account in the identification of crystals, and the 2θ value is preferably within ±0.3°, more preferably within ±0.2°, even more preferably within ±0.1°. For example, in the case of the description “a 2θ value shows a characteristic peak at 17.5°”, it means “a 2θ value shows a characteristic peak at 17.2° to 17.8°”. It is more preferable that “there is a characteristic peak at 17.3° to 17.7° as the 2θ value”, and “there is a characteristic peak at 17.4° to 17.6° as the 2θ value”. Is more preferable, and the same applies to other peaks.
　面間隔ｄ値の誤差範囲は、上述の２θ値の誤差範囲から算出される範囲を意味する。例えば、２θ値１７．５°に対応する面間隔ｄ値５．１Åの「面間隔ｄとして、５．１Åに特徴的なピークを示す」との記載の場合は、「面間隔ｄとして、５．０１Å～５．１９Åに特徴的なピークを示す」ことが好ましく、「面間隔ｄとして、５．０４Å～５．１６Åに特徴的なピークを示す」ことがより好ましく、「面間隔ｄとして、５．０７Å～５．１３Åに特徴的なピークを示す」ことが更に好ましく、他のピークについても同様である。 The error range of the surface spacing d value means a range calculated from the error range of the 2θ value described above. For example, in the case of the description of “the surface spacing d is 5.1 Å corresponding to the 2θ value of 17.5°, “the surface spacing d shows a characteristic peak at 5.1 Å”, “the surface spacing d is 5 It is preferable that "there is a characteristic peak at .01 Å to 5.19 Å", and it is more preferable that "there is a characteristic peak at 5.04 Å to 5.16 Å as the inter-spacing d". It is more preferable that “a characteristic peak appears at 5.07Å to 5.13Å”, and the same applies to other peaks.
　化合物（Ｉ）のアルコール和物の結晶は、赤外線吸収スペクトルにおいて、下記の通りの特徴的な吸収ピークを有するのが好ましい。 The crystal of the alcoholate of compound (I) preferably has the following characteristic absorption peak in the infrared absorption spectrum.
　化合物（Ｉ）のイソプロパノール和物の結晶は、波数１５３５cm－１及び１６３５cm－１付近に特徴的な吸収ピークを有するのが好ましい。別の観点からは、波数９４８cm－１、１０９６cm－１、１２４０cm－１及び１３８４cm－１付近に特徴的な吸収ピークを有するのが更に好ましい。 The crystal of the isopropanol solvate of the compound (I) preferably has characteristic absorption peaks near wave numbers of 1535 cm −1 and 1635 cm −1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 948 cm -1 , 1096 cm -1 , 1240 cm -1 and 1384 cm -1 .
　化合物（Ｉ）のエタノール和物の結晶は、波数１５３５cm－１及び１６２３cm－１付近に特徴的な吸収ピークを有するのが好ましい。別の観点からは、波数１０８４cm－１、１２４１cm－１及び１３８４cm－１付近に特徴的な吸収ピークを有するのが更に好ましい。 Crystals of the ethanol solvate of compound (I) preferably have characteristic absorption peaks near wave numbers of 1535 cm −1 and 1623 cm −1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 1084 cm -1 , 1241 cm -1 and 1384 cm -1 .
　化合物（Ｉ）のノルマルプロパノール和物の結晶は、波数１５３５cm－１及び１５８０cm－１付近に特徴的な吸収ピークを有するのが好ましい。別の観点からは、波数９６６cm－１、１０９４cm－１及び１３８４cm－１付近に特徴的な吸収ピークを有するのが更に好ましい。 The crystals of the normal propanol solvate of compound (I) preferably have characteristic absorption peaks near wave numbers of 1535 cm -1 and 1580 cm -1 . From another point of view, it is more preferable to have characteristic absorption peaks near the wave numbers of 966 cm -1 , 1094 cm -1 and 1384 cm -1 .
　上記波数の値は、特徴的な波数スケールを選択したものであり、必ずしもこれらの値だけによって限定されるものではなく、これら以外の波数スケールが含まれていてもよい。また一般に、赤外吸収スペクトル測定法は、測定機器又は測定条件等により、多少の測定誤差が生じ得るから、その特定には多少の誤差が考慮されるべきであり、波数の値は、波数スケールの±０．８％以内が好ましく、±０．５％以内がより好ましい。 The above-mentioned wave number values are selected from characteristic wave number scales, and are not necessarily limited only by these values, and wave number scales other than these may be included. In general, in the infrared absorption spectrum measurement method, some measurement error may occur due to measurement equipment or measurement conditions, and therefore some error should be taken into account in specifying the wave number. Within ±0.8% is preferable, and within ±0.5% is more preferable.
　本発明の化合物（Ｉ）のアルコール和物の結晶は、粉末Ｘ線回折において、２θ値として又は面間隔ｄとして前記の通りの特徴的なピークを示すものとして特定されるだけでなく、粉末Ｘ線回折における特徴的なピークに加えて、更に赤外線吸収スペクトルにおいて、前記の通りの特徴的な吸収ピークを有するものとして特定することができる。 The crystal of the alcoholate of the compound (I) of the present invention is not only specified as a characteristic peak as described above in the powder X-ray diffraction as the 2θ value or the interplanar spacing d, but also the powder X In addition to the characteristic peak in line diffraction, it can be specified as having a characteristic absorption peak as described above in the infrared absorption spectrum.
　化合物（Ｉ）のアルコール和物又はその結晶は、例えば以下の方法により製造することができる。
　化合物（Ｉ）は特許文献１乃至特許文献３に記載の方法等で製造することができる。化合物（Ｉ）のアルコール和物は、アルコール和物を製造するための通常の方法によって得ることができる。詳細には、化合物（Ｉ）のアルコール和物は、必要に応じて加熱しながらアモルファス状の化合物（Ｉ）とアルコールとを混和した後、撹拌又は放置しながらそれを冷却して結晶化させることにより得ることができる。冷却は、結晶の品質、粒度等への影響を考慮し、必要に応じて冷却速度を調節しながら実施することが望ましい。例えば、２０～１℃／時間の冷却速度で冷却するのが好ましく、１０～３℃／時間の冷却速度で冷却するのがより好ましい。これらの方法で使用されるアルコールの例としては、エタノール、ノルマルプロパノール及びイソプロパノール等が挙げられる。前記アルコールは含水でも良い。使用するアルコール量は、化合物（Ｉ）に対し、３～２０質量倍が好ましく、５～１０質量倍がより好ましい。 The alcoholate of compound (I) or a crystal thereof can be produced, for example, by the following method.
Compound (I) can be produced by the methods described in Patent Documents 1 to 3, and the like. The alcoholate of compound (I) can be obtained by a conventional method for producing an alcoholate. Specifically, the alcoholate of the compound (I) is obtained by mixing the amorphous compound (I) and the alcohol while heating, if necessary, and then cooling the mixture while stirring or leaving it to crystallize. Can be obtained by It is desirable that the cooling be carried out while adjusting the cooling rate as necessary in consideration of the influence on the crystal quality and grain size. For example, cooling at a cooling rate of 20 to 1° C./hour is preferable, and cooling at a cooling rate of 10 to 3° C./hour is more preferable. Examples of alcohols used in these methods include ethanol, normal propanol and isopropanol. The alcohol may be hydrous. The amount of alcohol used is preferably 3 to 20 times by mass, more preferably 5 to 10 times by mass, relative to the compound (I).
　化合物（Ｉ）のアルコール和物の結晶は、種結晶を化合物（Ｉ）のアルコール溶液に添加して得ることもできる。種結晶（例えば、化合物（Ｉ）のイソプロパノール和物の結晶）は、結晶化中に添加してもよい。種結晶が添加される温度は特に限定されないが、０～８０℃が好ましく、４０～７０℃がより好ましく、５０～６５℃が更に好ましい。種結晶の添加量は、化合物（Ｉ）１モルに対して、０．０００１～０．１モルが好ましく、０．００５～０．０１モルが更に好ましい。このような方法で、式（Ｉ）の化合物の、イソプロパノール和物の結晶、ノルマルプロパノール和物の結晶、又はエタノール和物の結晶等を得ることができる。 Crystals of the alcoholate of compound (I) can also be obtained by adding seed crystals to an alcohol solution of compound (I). Seed crystals (eg, crystals of isopropanol solvate of compound (I)) may be added during crystallization. The temperature at which the seed crystal is added is not particularly limited, but is preferably 0 to 80°C, more preferably 40 to 70°C, further preferably 50 to 65°C. The amount of seed crystals added is preferably 0.0001 to 0.1 mol, and more preferably 0.005 to 0.01 mol, per 1 mol of compound (I). By such a method, a crystal of isopropanol solvate, a crystal of normal propanol solvate, a crystal of ethanol solvate or the like of the compound of the formula (I) can be obtained.
　前記により得られた結晶は、通常の手順に従って、濾過単離し、必要に応じて洗浄し、更にそれを乾燥させることができる。結晶を洗浄するのに使用される溶媒としては、結晶化の際と同じ溶媒を使用することができる。 The crystals obtained above can be isolated by filtration, washed if necessary, and dried according to the usual procedure. As the solvent used for washing the crystals, the same solvent as used in the crystallization can be used.
　化合物（Ｉ）のアルコール和物は、結晶として得ることができるので、医薬品として取り扱いが容易になる。また、化合物（Ｉ）のアルコール和物は、いずれも吸湿性が化合物（Ｉ）のアモルファスと比較して低く、品質管理の点において医薬品として良好である。したがって、本発明によれば、医薬品原薬として有用である化合物（Ｉ）のアルコール和物を提供することができる。 Since the alcoholate of compound (I) can be obtained as crystals, it can be easily handled as a medicine. In addition, all of the alcoholates of compound (I) have lower hygroscopicity than the amorphous form of compound (I), and are good as pharmaceuticals in terms of quality control. Therefore, according to the present invention, an alcoholate of compound (I) which is useful as a drug substance can be provided.
　本発明の一実施形態に係る医薬組成物は、薬学的に許容される添加剤を化合物（Ｉ）のアルコール和物又はその結晶と混合することによって調製することができる。本発明の医薬組成物は、公知の方法によって、例えば日本薬局方第１７版の製剤総則に記載されている方法によって調製することができる。化合物（Ｉ）のアルコール和物又はその結晶を任意の割合で含む限り、アモルファス状の化合物（Ｉ）との混合物も、本発明に包含される。本発明の医薬組成物において、有効成分中の化合物（Ｉ）のアルコール和物又はその結晶の含有率は、２０％以上が好ましく、３０％以上がより好ましく、４０％以上が更に好ましく、１００％とすることが最も好ましい。 The pharmaceutical composition according to one embodiment of the present invention can be prepared by mixing a pharmaceutically acceptable additive with an alcoholate of compound (I) or a crystal thereof. The pharmaceutical composition of the present invention can be prepared by a known method, for example, the method described in the general rules for preparation of the 17th edition of the Japanese Pharmacopoeia. The present invention includes a mixture with the compound (I) in an amorphous form as long as it contains an alcoholate of the compound (I) or a crystal thereof in an arbitrary ratio. In the pharmaceutical composition of the present invention, the content of the alcoholate of the compound (I) or the crystal thereof in the active ingredient is preferably 20% or more, more preferably 30% or more, further preferably 40% or more, and 100%. Is most preferable.
　本発明の化合物（Ｉ）のアルコール和物又はその結晶は、Ｖ２受容体作動薬として作用することから、中枢性尿崩症、夜尿症、夜間頻尿、過活動膀胱、血友病、又はフォンウィルブランド病の予防又は治療のための医薬として使用することができる。尚、化合物（Ｉ）は、Ｖ２受容体に選択的に作用するため、副作用の観点から有利である。また、化合物（Ｉ）は、従来知られていたＶ２受容体作動作用を有する化合物に比べ、薬物代謝酵素ＣＹＰ３Ａ４及びＣＹＰ２Ｃ９に対する阻害作用が低いこと、更に、溶解度、膜透過性等の医薬品としての物性面や、血漿クリアランス及び分布容積といった動態面においても優れた性質を有しているため、安全に使用することができる。 Since the alcoholate of the compound (I) of the present invention or a crystal thereof acts as a V2 receptor agonist, central diabetes insipidus, nocturnal enuresis, nocturia, overactive bladder, hemophilia, or von Wille It can be used as a medicine for the prevention or treatment of Brand's disease. Compound (I) selectively acts on the V2 receptor and is therefore advantageous from the viewpoint of side effects. Further, the compound (I) has a lower inhibitory effect on the drug-metabolizing enzymes CYP3A4 and CYP2C9 than the conventionally known compounds having a V2 receptor agonistic action, and further has physical properties as a drug such as solubility and membrane permeability. Since it also has excellent properties in terms of surface and dynamic aspects such as plasma clearance and distribution volume, it can be used safely.
　医薬品の有効成分として含有される本発明の化合物（Ｉ）のアルコール和物又はその結晶の量は、特に限定されず、広範囲より適宜選択される。化合物（Ｉ）のアルコール和物又はその結晶の投与量は、その用法、患者の年齢、性別その他の条件、疾患の程度により適宜決定されるが、経口投与の場合には、１日量が体重１ｋｇ当り約１μｇ～１００ｍｇ、好ましくは約１０μｇ～２０ｍｇが適当で、更に好ましくは約５０μｇ～５ｍｇが適当であり、これを１日に１～４回に分けて適宜投与することができる。しかしながら、投与量、回数は、治療すべき症状の程度、投与される化合物の選択及び選択された投与経路を含む関連する状況に鑑みて決定されることから、前記の投与量範囲及び回数は本発明の範囲を限定するものではない。 The amount of the alcohol solvate of the compound (I) of the present invention or its crystal contained as an active ingredient of a drug is not particularly limited and is appropriately selected from a wide range. The dose of the alcohol solvate of Compound (I) or the crystal thereof is appropriately determined depending on the usage, the age of the patient, sex and other conditions, and the degree of the disease. Approximately 1 μg to 100 mg, preferably approximately 10 μg to 20 mg, and more preferably approximately 50 μg to 5 mg per kg, which can be appropriately administered in 1 to 4 divided doses per day. However, since the dose and frequency are determined in consideration of the degree of the condition to be treated, the selection of the compound to be administered and the relevant circumstances including the selected administration route, the above dose range and frequency are not limited to the above. It does not limit the scope of the invention.
　化合物（Ｉ）は、生体に投与した場合、下記に示すような代謝物を生じる。
Figure JPOXMLDOC01-appb-C000005
 Compound (I) produces metabolites as shown below when administered to a living body.
Figure JPOXMLDOC01-appb-C000005
　以下に、参考例、実施例、比較例及び試験例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定されるものではない。 The present invention will be described more specifically below with reference to Reference Examples, Examples, Comparative Examples and Test Examples, but the present invention is not limited to these.
　粉末Ｘ線回折測定、熱重量測定、赤外吸収スペクトル測定、及び水分平衡測定は、以下の測定条件で行った。 The powder X-ray diffraction measurement, thermogravimetric measurement, infrared absorption spectrum measurement, and water equilibrium measurement were performed under the following measurement conditions.
［粉末Ｘ線回折測定］
　粉末Ｘ線回折測定は、理学電機製を使用して行なった。銅放射線を放射線として用い、測定条件は、管電流１５ｍＡ、管電圧３０ｋＶ、発散スリットＶａｒｉａｂｌｅ、散乱スリット４．２ｄｅｇ、受光スリット０．３ｍｍ、走査範囲５．００～４０．００°、走査速度２°／ｍｉｎとした。 [Powder X-ray diffraction measurement]
The powder X-ray diffraction measurement was performed using a product manufactured by Rigaku Denki. Copper radiation was used as radiation, and the measurement conditions were as follows: tube current 15 mA, tube voltage 30 kV, divergence slit Variable, scattering slit 4.2 deg, light receiving slit 0.3 mm, scanning range 5.00 to 40.00°, scanning speed 2°. /Min.
［熱重量測定］
　ＴＧＡサーモグラムは、パーキンエルマー製（Ｐｙｒｉｓ１－ＴＧＡ）を使用して行った。測定条件は、窒素ガス２０ｍＬ／分、初期温度８０℃で１分等温後、５℃／分で１７０℃まで昇温し、１７０℃で１分等温とした。 [Thermogravimetric measurement]
The TGA thermogram was performed using Perkin Elmer (Pyris1-TGA). The measurement conditions were 20 mL/min of nitrogen gas, isothermal for 1 minute at an initial temperature of 80° C., then increased to 170° C. at 5° C./minute, and isothermal for 1 minute at 170° C.
［赤外吸収スペクトル測定］
　赤外吸収スペクトル測定は、パーキンエルマー社製（Ｓｐｅｃｔｒｕｍ　Ｏｎｅ）を使用して行った。測定条件は、測定範囲４０００～４００cm－１、分解能４．００cm－１、スキャン回数は４回とした。 [Infrared absorption spectrum measurement]
The infrared absorption spectrum was measured using Perkin Elmer (Spectrum One). Measurement conditions, the measurement range 4000 ~ 400 cm -1, resolution 4.00 cm -1, scan number was 4 times.
［水分平衡測定］
　水分平衡測定は、ＴＡ Ｉｎｓｔｒｕｍｅｎｔｓ社製（ＳＧＡ－１００）を使用して行なった。測定条件は、測定温度２５℃、最大測定時間２１０分、水分平衡重量０．００５重量％／５分、加湿開始から終了点までは５０～９５％ＲＨとした。乾燥条件は、乾燥温度６０℃、昇温率５℃／分、最大乾燥時間６０分、水分平衡重量０．０１重量％／２分とした。 [Water equilibrium measurement]
The moisture equilibrium measurement was performed using TA Instruments (SGA-100). The measurement conditions were a measurement temperature of 25° C., a maximum measurement time of 210 minutes, a water equilibrium weight of 0.005% by weight/5 minutes, and 50 to 95% RH from the start of humidification to the end point. The drying conditions were a drying temperature of 60° C., a temperature rising rate of 5° C./minute, a maximum drying time of 60 minutes, and a water equilibrium weight of 0.01% by weight/2 minutes.
［参考例１］化合物（Ｉ）（アモルファス）
　化合物（Ｉ）は、以下の方法により製造した。
Figure JPOXMLDOC01-appb-C000006
 [Reference Example 1] Compound (I) (amorphous)
Compound (I) was produced by the following method.
Figure JPOXMLDOC01-appb-C000006
（第１工程）
　１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－５－オキソ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルを、臭化ベンゼン、水混合溶媒中、（Ｒ，Ｒ）－３，５－ビストリフルオロメチルフェニル－ＮＡＳブロミド、炭酸セシウム、フッ化セシウム存在下、臭化メチルを用いてメチル化を行うことで（Ｒ）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－５－オキソ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルを得た。 (First step)
1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carvone Methylation of acid ethyl ester with methyl bromide in the presence of (R,R)-3,5-bistrifluoromethylphenyl-NAS bromide, cesium carbonate and cesium fluoride in a mixed solvent of benzene bromide and water. (R)-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro- 1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained.
（第２工程）
　（Ｒ）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－５－オキソ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルのケトン部分をトルエン溶媒中、水素化ホウ素ナトリウムと硫酸アンモニウムから調製したボラン・アンモニア錯体を用いて還元することで、（４Ｒ）－５－ヒドロキシ－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルを得た。 (Second step)
(R)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-benzo [B] Reduction of the ketone moiety of azepine-4-carboxylic acid ethyl ester with a borane-ammonia complex prepared from sodium borohydride and ammonium sulfate in a toluene solvent to give (4R)-5-hydroxy-4- Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate ethyl ester The ester was obtained.
（第３工程）
　（４Ｒ）－５－ヒドロキシ－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルのヒドロキシル基をトルエン溶媒中、ピリジン存在下、オキシ塩化リンでクロロ化することで（４Ｓ）－５－クロロ－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルを得た。 (Third step)
(4R)-5-Hydroxy-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo [B] Chlorination of the hydroxyl group of azepine-4-carboxylic acid ethyl ester with phosphorus oxychloride in the presence of pyridine in a toluene solvent to give (4S)-5-chloro-4-methyl-1-(2-methyl -4-(3-Methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained.
（第４工程）
　（４Ｓ）－５－クロロ－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルをメタノール溶媒中、１０％パラジウム－炭素存在下、水素ガスの微加圧条件下で撹拌することで（Ｓ）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルを得た。 (Fourth step)
(4S)-5-Chloro-4-methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo [B] Azepine-4-carboxylic acid ethyl ester was stirred in a methanol solvent in the presence of 10% palladium-carbon under slightly pressurized conditions of hydrogen gas to obtain (S)-4-methyl-1-(2- Methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethyl ester was obtained.
（第５工程）
　（Ｓ）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸エチルエステルを水、メタノール溶媒中、３０％水酸化ナトリウムを用いて加水分解することで（Ｓ）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸を得た。 (Fifth step)
(S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -4-carboxylic acid ethyl ester was hydrolyzed with 30% sodium hydroxide in a solvent of water and methanol to give (S)-4-methyl-1-(2-methyl-4-(3-methyl-1H). -Pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid was obtained.
（第６工程）
　（Ｓ）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボン酸をトルエン溶媒中、塩化チオニルを用いて酸クロリド体とした。この酸クロリド体とＬ－アラニノールを酢酸エチル、水混合溶媒中で炭酸ナトリウム存在下、反応させることで（Ｓ）－Ｎ－（（Ｓ）－１－ヒドロキシプロパン－２－イル）－４－メチル－１－（２－メチル－４－（３－メチル－１Ｈ－ピラゾール－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボキサミド（化合物（Ｉ））を得た。 (Sixth step)
(S)-4-Methyl-1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -4-Carboxylic acid was converted to an acid chloride using thionyl chloride in a toluene solvent. This acid chloride and L-alaninol are reacted in a mixed solvent of ethyl acetate and water in the presence of sodium carbonate to give (S)-N-((S)-1-hydroxypropan-2-yl)-4-methyl. -1-(2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide (compound ( I)) was obtained.
　前記第１工程～第６工程で得られた化合物（Ｉ）の粉末Ｘ線回折スペクトルを図７に示す。Ｘ線回折パターンにおいて、明確なピークが観測されず、参考例１の化合物（Ｉ）はアモルファスであることが判明した。 FIG. 7 shows the powder X-ray diffraction spectrum of the compound (I) obtained in the first to sixth steps. No clear peak was observed in the X-ray diffraction pattern, and the compound (I) of Reference Example 1 was found to be amorphous.
［実施例１］化合物（Ｉ）のイソプロパノール和物
　参考例１のアモルファスの化合物（Ｉ）５．０ｇに対し、イソプロパノール６５ｍＬを加え、室温で３０分間撹拌した。析出した懸濁液を加温溶解させた後、室温まで放冷し、５℃で一晩撹拌した。懸濁液をろ過し、冷却したイソプロパノールで洗浄し、４０℃で一晩乾燥することで、白色固体４．９ｇを得た。 [Example 1] Isopropanol solvate of compound (I) To 5.0 g of the amorphous compound (I) of Reference Example 1, 65 mL of isopropanol was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with chilled isopropanol and dried overnight at 40° C. to give 4.9 g of a white solid.
　得られた化合物を熱重量装置で分析したところ、イソプロパノールの含有量は、化合物（Ｉ）に対して８．２％であり、モル比で化合物（Ｉ）に対して０．７倍量であった。 When the obtained compound was analyzed by a thermogravimetric apparatus, the content of isopropanol was 8.2% based on the compound (I), and the molar ratio was 0.7 times the amount based on the compound (I). It was
　実施例１で得られた化合物の粉末Ｘ線回折スペクトルを図１に、赤外線吸収スペクトルを図２に示す。回折角（２θ）として又は面間隔ｄとして、表１に記載の特徴的なピークを示した。得られた化合物は結晶であった。 The powder X-ray diffraction spectrum and infrared absorption spectrum of the compound obtained in Example 1 are shown in FIG. 1 and FIG. 2, respectively. The characteristic peaks shown in Table 1 were shown as the diffraction angle (2θ) or as the interplanar spacing d. The obtained compound was crystalline.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
［実施例２］化合物（Ｉ）のエタノール和物
　参考例１のアモルファスの化合物（Ｉ）０．１５ｇに対し、エタノール２ｍＬを加え、室温で３０分間撹拌した。析出した懸濁液を加温溶解させた後、室温まで放冷し、５℃で一晩撹拌した。懸濁液をろ過し、冷却したエタノールで洗浄し、４０℃で一晩乾燥することで、白色固体０．０７ｇを得た。 [Example 2] Ethanol solvate of compound (I) To 0.15 g of the amorphous compound (I) of Reference Example 1, 2 mL of ethanol was added, and the mixture was stirred at room temperature for 30 minutes. After the precipitated suspension was dissolved by heating, it was allowed to cool to room temperature and stirred at 5°C overnight. The suspension was filtered, washed with cold ethanol, and dried at 40° C. overnight to give white solid 0.07 g.
　得られた化合物を熱重量装置で分析したところ、エタノールの含有量は、化合物（Ｉ）に対して５．７％であり、モル比で化合物（Ｉ）に対して０．６倍量であった。 When the obtained compound was analyzed by a thermogravimetric apparatus, the content of ethanol was 5.7% with respect to the compound (I), and the molar ratio was 0.6 times the amount with respect to the compound (I). It was
　実施例２で得られた化合物の粉末Ｘ線回析スペクトルを図３に、赤外線吸収スペクトルを図４に示す。回折角（２θ）として又は面間隔ｄとして、表２に記載の特徴的なピークを示した。得られた化合物は結晶であった。 The powder X-ray diffraction spectrum and infrared absorption spectrum of the compound obtained in Example 2 are shown in FIG. 3 and FIG. 4, respectively. The characteristic peaks shown in Table 2 were shown as the diffraction angle (2θ) or as the interplanar spacing d. The obtained compound was crystalline.
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
［実施例３］化合物（Ｉ）のノルマルプロパノール和物
　参考例１のアモルファスの化合物（Ｉ）５．０ｇに対し、ノルマルプロパノール３１ｍＬを加え、室温で１５分間撹拌した。析出した懸濁液を加温溶解させた後、室温まで放冷し、５℃で一晩撹拌した。懸濁液をろ過し、冷却したノルマルプロパノールで洗浄し、４０℃で一晩乾燥することで、白色固体４．１ｇを得た。 [Example 3] Normal propanol solvate of compound (I) To 5.0 g of amorphous compound (I) of Reference Example 1, 31 mL of normal propanol was added, and the mixture was stirred at room temperature for 15 minutes. The precipitated suspension was heated and dissolved, and then allowed to cool to room temperature and stirred overnight at 5°C. The suspension was filtered, washed with cold normal propanol, and dried at 40° C. overnight to obtain 4.1 g of a white solid.
　得られた化合物を熱重量装置で分析したところ、ノルマルプロパノールの含有量は、化合物（Ｉ）に対して８．１％であり、モル比で化合物（Ｉ）に対して０．７倍量であった。 When the obtained compound was analyzed by a thermogravimetric apparatus, the content of normal propanol was 8.1% based on the compound (I), and the molar ratio was 0.7 times the amount based on the compound (I). there were.
　実施例３で得られた化合物の粉末Ｘ線回折スペクトルを図５に、赤外線吸収スペクトルを図６に示す。回折角（２θ）として又は面間隔ｄとして、表３に記載の特徴的なピークを示した。得られた化合物は結晶であった。 A powder X-ray diffraction spectrum and an infrared absorption spectrum of the compound obtained in Example 3 are shown in FIG. 5 and FIG. 6, respectively. The characteristic peaks shown in Table 3 were shown as the diffraction angle (2θ) or as the interplanar spacing d. The obtained compound was crystalline.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
［比較例１］４－フルオロ－Ｎ－（（Ｓ）－１－ヒドロキシプロパン－２－イル）－１－（２－メチル－４－（ピロリジン－１－イル）ベンゾイル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボキサミドの結晶化検討
Figure JPOXMLDOC01-appb-C000010
 Comparative Example 1 4-Fluoro-N-((S)-1-hydroxypropan-2-yl)-1-(2-methyl-4-(pyrrolidin-1-yl)benzoyl)-2,3,4 Of crystallization of 2,5-tetrahydro-1H-benzo[b]azepine-4-carboxamide
Figure JPOXMLDOC01-appb-C000010
　特許文献１の実施例９３に記載の化合物（比較化合物１：前記式(II)で示される化合物）を、特許文献１に記載の製法で得た。得られた比較化合物１　１０ｍｇに対し、表４に記載の溶媒を加え、室温で撹拌、加温溶解させた後、室温まで放冷し、５℃で一晩静置した。しかしながら、比較化合物１の溶媒和物及びその結晶を得ることはできなかった。 The compound described in Example 93 of Patent Document 1 (Comparative compound 1: the compound represented by the above formula (II)) was obtained by the production method described in Patent Document 1. To 10 mg of the obtained comparative compound 1, the solvent shown in Table 4 was added, and the mixture was stirred at room temperature, dissolved by heating, allowed to cool to room temperature, and allowed to stand at 5° C. overnight. However, it was not possible to obtain a solvate of Comparative Compound 1 or a crystal thereof.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
［比較例２］１－（２－クロロ－４－（３－メチル－１Ｈ－ピラゾール－１－イル）－Ｎ－（（Ｓ）－１－ヒドロキシプロパン－２－イル）－４－メチル－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｂ］アゼピン－４－カルボキサミドの結晶化検討
Figure JPOXMLDOC01-appb-C000012
 [Comparative Example 2] 1-(2-chloro-4-(3-methyl-1H-pyrazol-1-yl)-N-((S)-1-hydroxypropan-2-yl)-4-methyl-2 Study of 1,3,4,5-Tetrahydro-1H-benzo[b]azepine-4-carboxamide
Figure JPOXMLDOC01-appb-C000012
　特許文献１の実施例７２に記載の化合物（比較化合物２：前記式（III）で示される化合物）を、特許文献１に記載の製法で得た。得られた比較化合物２　１０ｍｇに対し、表５に記載の溶媒を加え、室温で撹拌、加温溶解させた後、室温まで放冷し、５℃で一晩静置した。しかしながら、比較化合物２の溶媒和物及びその結晶を得ることはできなかった。 The compound described in Example 72 of Patent Document 1 (Comparative compound 2: compound represented by the above formula (III)) was obtained by the production method described in Patent Document 1. The solvent shown in Table 5 was added to 10 mg of the obtained comparative compound 2, and the mixture was stirred at room temperature, dissolved by heating, allowed to cool to room temperature, and allowed to stand at 5° C. overnight. However, it was not possible to obtain a solvate of Comparative Compound 2 or a crystal thereof.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
［試験例１］吸湿性試験
　実施例１の化合物（化合物（Ｉ）のイソプロパノール和物）、実施例２の化合物（化合物（Ｉ）のエタノール和物）、及び参考例１の化合物（アモルファスの化合物（Ｉ））の吸湿性を、以下の条件下で比較した。 Test Example 1 Hygroscopicity Test The compound of Example 1 (isopropanol solvate of compound (I)), the compound of Example 2 (ethanol solvate of compound (I)), and the compound of Reference Example 1 (amorphous compound) The hygroscopicity of (I)) was compared under the following conditions.
　天秤に石英製サンプルホルダーを釣り掛け、実施例１及び２、並びに参考例１の化合物約１０ｍｇを入れた。サンプル質量を登録後、水分平衡測定装置により試験を行い、各相対湿度における質量の変化率を測定した。 A quartz sample holder was hooked on a balance, and about 10 mg of the compounds of Examples 1 and 2 and Reference Example 1 were put therein. After registering the sample mass, a test was carried out with a water balance measuring device to measure the rate of change of mass at each relative humidity.
　試験例１の結果を図８に示す。参考例１の化合物と比較して、実施例１及び実施例２の化合物は吸湿しにくく、保存安定性に優れていることが確認された。 The results of Test Example 1 are shown in FIG. It was confirmed that the compounds of Examples 1 and 2 were less likely to absorb moisture and were excellent in storage stability as compared with the compound of Reference Example 1.
　今回開示された実施の形態はすべての点で例示であって、制限的なものではないと考えられるべきである。本発明の範囲は上記した説明ではなく特許請求の範囲によって示され、特許請求の範囲と均等の意味、及び範囲内でのすべての変更が含まれることが意図される。 The embodiments disclosed this time are to be considered as illustrative in all points and not restrictive. The scope of the present invention is shown not by the above description but by the scope of the claims, and is intended to include meanings equivalent to the scope of the claims and all modifications within the scope.
　本発明によって、式（Ｉ）で表される光学活性なベンゾアゼピン誘導体のアルコール和物を結晶として単離することができる。 According to the present invention, an alcoholate of an optically active benzazepine derivative represented by the formula (I) can be isolated as a crystal.

Claims (16)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     で示される化合物のアルコール和物又はその結晶。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     An alcoholate of the compound shown by or a crystal thereof.
  2. 　アルコールの含有量が、前記式（Ｉ）で示される化合物に対してモル比で０．１倍量から２倍量である、請求項１に記載のアルコール和物又はその結晶。 The alcohol solvate or the crystal thereof according to claim 1, wherein the alcohol content is 0.1 to 2 times the molar amount of the compound represented by the formula (I).
  3. 　前記アルコールが、エタノール、イソプロパノール、及びノルマルプロパノールからなる群より選択される、請求項１又は２に記載のアルコール和物又はその結晶。 The alcohol solvate or the crystal thereof according to claim 1 or 2, wherein the alcohol is selected from the group consisting of ethanol, isopropanol, and normal propanol.
  4. 　前記アルコールがイソプロパノールである、請求項３に記載のアルコール和物又はその結晶。 The alcohol solvate or the crystal thereof according to claim 3, wherein the alcohol is isopropanol.
  5. 　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、回折角度２θ±０．３°として、１７．５°及び１８．０°に特徴的なピークを示すか、８．５°、１４．８°、１８．０°及び２１．０°に特徴的なピークを示すか、８．５°、１１．９°、１４．１°、１４．８°、１７．５°、１８．０°及び２１．０°に特徴的なピークを示すか、又は８．５°、１１．９°、１４．１°、１４．８°、１７．５°、１８．０°、１９．０°、２０．７°、２１．０°、２２．８°及び２４．６°に特徴的なピークを示す、請求項４に記載のアルコール和物の結晶。 In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, characteristic peaks are shown at 17.5° and 18.0° as diffraction angles 2θ±0.3°, or 8.5°, 14.°. Shows characteristic peaks at 8°, 18.0° and 21.0° or 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, 18.0°. And characteristic peaks at 21.0° or 8.5°, 11.9°, 14.1°, 14.8°, 17.5°, 18.0°, 19.0°, The alcohol solvate crystal according to claim 4, which exhibits characteristic peaks at 20.7°, 21.0°, 22.8°, and 24.6°.
  6. 　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、５．１±０．０９Å及び４．９±０．０８Åに特徴的なピークを示すか、１０．３±０．３７Å、６．０±０．１２Å、４．９±０．０８Å及び４．２±０．０６Åに特徴的なピークを示すか、１０．３±０．３７Å、７．４±０．１９Å、６．３±０．１３Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å及び４．２±０．０６Åに特徴的なピークを示すか、又は１０．３±０．３７Å、７．４±０．１９Å、６．３±０．１３Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å、４．７±０．０７Å、４．３±０．０６Å、４．２±０．０６Å、３．９±０．０５Å及び３．６±０．０４Åに特徴的なピークを示す、請求項４に記載のアルコール和物の結晶。 In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, characteristic peaks at 5.1±0.09Å and 4.9±0.08Å as the d-spacing are shown, or 10.3±0. 37 Å, 6.0 ± 0.12 Å, 4.9 ± 0.08 Å and 4.2 ± 0.06 Å characteristic peaks, 10.3 ± 0.37 Å, 7.4 ± 0.19 Å, Shows characteristic peaks at 6.3±0.13Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å and 4.2±0.06Å, or 10 .3±0.37Å, 7.4±0.19Å, 6.3±0.13Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å, 4.7 5. The method according to claim 4, wherein the characteristic peaks are ±0.07Å, 4.3±0.06Å, 4.2±0.06Å, 3.9±0.05Å and 3.6±0.04Å. Crystal of alcohol solvate.
  7. 　赤外線吸収スペクトルにおいて、波数（±０．５％）として、１５３５cm－１及び１６３５cm－１に特徴的な吸収ピークを示すか、又は９４８cm－１、１０９６cm－１、１２４０cm－１及び１３８４cm－１に特徴的な吸収ピークを示す、請求項４～６のいずれか一項に記載のアルコール和物の結晶。 Wherein in the infrared absorption spectrum, as wavenumber (± 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1635 cm -1, or 948cm -1, 1096cm -1, to 1240 cm -1 and 1384cm -1 The crystal of the alcoholate according to any one of claims 4 to 6, which exhibits a specific absorption peak.
  8. 　前記アルコールがエタノールである、請求項３に記載のアルコール和物又はその結晶。 The alcohol solvate or the crystal thereof according to claim 3, wherein the alcohol is ethanol.
  9. 　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、回折角度２θ±０．３°として、８．９°、１２．１°、１４．３°、１８．２°及び２１．４°に特徴的なピークを示すか、又は８．９°、９．４°、１２．１°、１４．３°、１５．１°、１８．２°、２０．９°、２１．４°及び２３．１°に特徴的なピークを示す、請求項８に記載のアルコール和物の結晶。 In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, the diffraction angles 2θ±0.3° were 8.9°, 12.1°, 14.3°, 18.2° and 21.4°. Shows characteristic peaks or 8.9°, 9.4°, 12.1°, 14.3°, 15.1°, 18.2°, 20.9°, 21.4° and 23 The crystal of the alcohol solvate according to claim 8, which exhibits a characteristic peak at 0.1°.
  10. 　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、１０．０±０．３３Å、７．３±０．１８Å、６．２±０．１３Å、４．９±０．０８Å及び４．１±０．０６Åに特徴的なピークを示すか、又は１０．０±０．３３Å、９．４±０．３０Å、７．３±０．１８Å、６．２±０．１３Å、５．９±０．１２Å、４．９±０．０８Å、４．３±０．０６Å、４．１±０．０６Å及び３．９±０．０５Åに特徴的なピークを示す、請求項８に記載のアルコール和物の結晶。 In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, the spacing d was 10.0±0.33Å, 7.3±0.18Å, 6.2±0.13Å, 4.9±0. Shows characteristic peaks at 08Å and 4.1±0.06Å, or 10.0±0.33Å, 9.4±0.30Å, 7.3±0.18Å, 6.2±0.13Å Claim 5.9±0.12Å, 4.9±0.08Å, 4.3±0.06Å, 4.1±0.06Å and 3.9±0.05Å A crystal of the alcohol solvate according to item 8.
  11. 　赤外線吸収スペクトルにおいて、波数（±０．５％）として、１５３５cm－１及び１６２３cm－１に特徴的な吸収ピークを示すか、又は１０８４cm－１、１２４１cm－１及び１３８４cm－１に特徴的な吸収ピークを示す、請求項８～１０のいずれか一項に記載のアルコール和物の結晶。 In the infrared absorption spectrum, as wavenumber (± 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1623cm -1, or 1084Cm -1, characteristic absorption peaks at 1241cm -1 and 1384cm -1 The crystal of the alcohol solvate according to any one of claims 8 to 10, wherein
  12. 　前記アルコールがノルマルプロパノールである、請求項３に記載のアルコール和物又はその結晶。 The alcohol solvate or the crystal thereof according to claim 3, wherein the alcohol is normal propanol.
  13. 　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、回折角度２θ±０．３°として、１７．３°、１８．０°及び１８．８°に特徴的なピークを示すか、８．５°、１４．８°、１８．０°及び２１．０°に特徴的なピークを示すか、８．５°、１４．８°、１７．３°、１８．０°、１８．８°及び２１．０°に特徴的なピークを示すか、又は８．５°、１１．９°、１４．３°、１４．８°、１７．３°、１８．０°、１８．８°、２１．０°、２２．２°、２２．７°、２３．０°及び２４．５°に特徴的なピークを示す、請求項１２に記載のアルコール和物の結晶。 7. A powder X-ray diffraction spectrum (pattern) using CuKα radiation shows characteristic peaks at 17.3°, 18.0°, and 18.8° at a diffraction angle of 2θ±0.3°, or 8. Shows characteristic peaks at 5°, 14.8°, 18.0° and 21.0°, or 8.5°, 14.8°, 17.3°, 18.0°, 18.8°. And 21.0° or characteristic peaks at 8.5°, 11.9°, 14.3°, 14.8°, 17.3°, 18.0°, 18.8°, The alcohol solvate crystal according to claim 12, which exhibits characteristic peaks at 21.0°, 22.2°, 22.7°, 23.0°, and 24.5°.
  14. 　ＣｕＫα放射を用いた粉末Ｘ線回折スペクトル（パターン）において、面間隔ｄとして、５．１±０．０９Å、４．９±０．０８Å及び４．７±０．０７Åに特徴的なピークを示すか、１０．４±０．３７Å、６．０±０．１２Å、４．９±０．０８Å及び４．２±０．０６Åに特徴的なピークを示すか、１０．４±０．３７Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å、４．７±０．０７Å及び４．２±０．０６Åに特徴的なピークを示すか、又は１０．４±０．３７Å、７．４±０．１９Å、６．２±０．１３Å、６．０±０．１２Å、５．１±０．０９Å、４．９±０．０８Å、４．７±０．０７Å、４．２±０．０６Å、４．０±０．０５Å、３．９±０．０５Å及び３．６±０．０４Åに特徴的なピークを示す、請求項１２に記載のアルコール和物の結晶。 In the powder X-ray diffraction spectrum (pattern) using CuKα radiation, characteristic peaks at 5.1±0.09Å, 4.9±0.08Å and 4.7±0.07Å are shown as the interplanar spacing d. Or 10.4±0.37Å, 6.0±0.12Å, 4.9±0.08Å and 4.2±0.06Å show characteristic peaks, 10.4±0.37Å, It shows characteristic peaks at 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å, 4.7±0.07Å and 4.2±0.06Å, or 10 .4±0.37Å, 7.4±0.19Å, 6.2±0.13Å, 6.0±0.12Å, 5.1±0.09Å, 4.9±0.08Å, 4.7 13. The method according to claim 12, which shows characteristic peaks at ±0.07Å, 4.2±0.06Å, 4.0±0.05Å, 3.9±0.05Å and 3.6±0.04Å. Crystal of alcohol solvate.
  15. 　赤外線吸収スペクトルにおいて、波数（±０．５％）として、１５３５cm－１及び１５８０cm－１に特徴的な吸収ピークを示すか、又は９６６cm－１、１０９４cm－１及び１３８４cm－１に特徴的な吸収ピークを示す、請求項１２～１４のいずれか一項に記載のアルコール和物の結晶。 In the infrared absorption spectrum, as wavenumber (± 0.5%), or shows a characteristic absorption peak at 1535cm -1 and 1580 cm -1, or 966cm -1, characteristic absorption peaks at 1094 cm -1 and 1384cm -1 The crystal of the alcohol solvate according to any one of claims 12 to 14, which exhibits
  16. 　請求項１～１５のいずれか一項に記載のアルコール和物又はその結晶を含む医薬組成物。 A pharmaceutical composition comprising the alcoholate or the crystal thereof according to any one of claims 1 to 15.
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WO2014104209A1 (en) * 2012-12-26 2014-07-03 株式会社 三和化学研究所 Novel benzazepine derivative and pharmaceutical use thereof

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WO2014104209A1 (en) * 2012-12-26 2014-07-03 株式会社 三和化学研究所 Novel benzazepine derivative and pharmaceutical use thereof

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"About standards for new drugs and setting of a test method", PHARMACEUTICAL AFFAIRS BUREAU NOTIFICATION NO. 568, 2001 *
GRIESSER, U. J.: "The Importance of Solvates", POLYMORPHISM: IN THE PHARMACEUTICAL INDUSTRY, 2006, pages 211 - 233, XP055582446 *

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